Affiliation: Wyeth Research: Cardiovascular and Metabolic Diseases 200 Cambridge Park Drive Cambridge, Massachusetts 02140, USA.
The extravasation of leukocytes from the vascular to the interstitial compartment is a hallmark of the inflammatory response and is associated with the pathogenesis of many cardiovascular and immune-related diseases. Prior to their migration through the vessel wall, leukocytes undergo a series of adhesive interactions that begin as a rolling movement along the vascular endothelium, and are succeeded by stationary firm adhesion to the vessel wall. These rolling interactions are mediated primarily through low affinity interactions via the selectin (E-, L- and P-selectin) family of cell adhesion molecules, whereas firm adhesion between leukocytes and endothelial cells is mediated by the supergene immunoglobulins located on the surface on endothelial cells and their ligands, the integrins (β1, β2), located on leukocytes. The development of monoclonal antibodies and gene-targeted mice aimed at neutralizing these adhesive interactions have become powerful tools in examining the consequences of interfering with leukocyte-endothelial cell adhesion in the progression of many diseases, and validating their inhibition as a therapeutic targets. In recent years, significant efforts in developing small molecule antagonists and protein-engineered inhibitors against the selectins and integrin cell adhesion molecule families have been made. In this review, the available evidence concerning the role of leukocyte-endothelial cell adhesion in mediating vascular dysfunction and tissue necrosis in inflammatory diseases will be examined. Specifically, the development of leukocyte-endothelial cell adhesion inhibitors for the treatment of inflammatory diseases and their therapeutic benefits will be addressed.